There are six known herpes-type viruses which affect human beings: herpes zoster (chicken pox), herpes simplex virus I & II (cold sores and genital herpes), cytomegalovirus (cytomegalic inclusion disease), Epstein-Barr virus (mononucleosis), and the recently isolated Herpes VI virus. The herpes viruses are medium-sized viruses containing double-stranded DNA, with a nucleocapsid about 100 nm in diameter surrounded by a lipid-containing envelope. The virion is 150-200 nm in diameter and permits latent infections which last for the life span of the host even when antibodies are present.
Purine-based analogs to treat herpes infections are known and have been described, for example, in U.S. Pat. No. 4,808,716 to Hol et al. and U.S. Pat. Nos. 4,755,516 and 4,897,479 to Tolman et al. The Hol et al. patent relates to 9-(phosphonylmethoxyalkyl)adenines and their use in treating herpes simplex virus, types I & II, while the Tolman et al. disclosures describe a family of 6-substituted purines which are stated to be useful against herpes viruses in general. U.S. Pat. No. 5,047,533 to Reist et al., of common assignment herewith, also describes purine analogs which have antiviral activity against the Herpes group of viruses. The present invention relates to and indeed derives from the work carried out in the aforementioned patent, and reference may be had thereto for information related to the present invention but not explicitly mentioned herein. Accordingly, the disclosure of U.S. Pat. No. 5,047,533 to Reist et al. is incorporated by reference in its entirety.
The antiviral agents of the present invention, like those of U.S. Pat. No. 5,047,533 to Reist et al., are acyclic purine phosphonate nucleotide analogs. In addition to the patents cited in the preceding paragraph, the following reference describes a large number of phosphonate analogs of nucleotides: R. Engle, Chem. Reviews 11(3):349-367 (1977). Phosphonate compounds which are direct cyclic nucleotide analogs are also disclosed in: U.S. Pat. No. 3,560,478 to Myers et al.; German Patent Application No. DE 3,045,375VA1, published Jul. 1, 1982; U.S. Pat. No. 3,446,793 to Jones et al.; British Patent Nos. 1,243,213 and 1,243,214; German Patent Application No. 2,009,834, published Sep. 17, 1970; A. Hampton et al., Biochemistry 12:1730-1736 (1973); G. H. Jones et al., J. Am. Chem. Soc. 90:5337-5338 (1968); and J. A. Montgomery et al., J. Med. Chem. 22:109-111 (1979).
Other references of interest include EPO Publication No. 173,624, published May 3, 1986, which discloses 9(3-phosphono-1-propoxymethyl)guanine as an anti-herpes agent, and A. E. Duke et al., Antiviral Res. 6:299-308 (1986) and E. J. Prisbe et al., J. Med. Chem. 29:671-675 (1986), which relate to 9(3-phosphono-1-hydroxymethyl-1-propoxymethyl) guanine.
The present invention in a first aspect relates to methods for making the acyclic purine phosphonate nucleotide analogs of the '533 patent in enantiomerically pure form. Prior to the development of the synthetic method described and claimed herein, neither isolation nor synthesis of the pure enantiomers was feasible. In another aspect, then, the invention encompasses enantiomerically pure acyclic purine phosphonate nucleotide analogs as novel compounds. Indeed, it has now been found that at least one of the isolated enantiomers--the "R" enantiomer--has significant activity against several herpes viruses. In still another aspect, the invention relates to the implementation of the aforementioned synthetic method--which may be used to make pure enantiomers, as noted above--to prepare the racemic mixture of acyclic purine phosphonate nucleotide analogs described in U.S. Pat. No. 5,047,533 to Reist et al., cited and incorporated by reference above.